The human ear is comprised of three major structural components: the outer, middle, and inner ears, which function together to convert sound waves into nerve impulses that travel to the brain, where they are perceived as sound. The inner ear also helps to maintain balance.
The anatomy of the middle and the inner ear is well known to those of ordinary skill in the art (see, e.g., Atlas of Sensory Organs: Functional and Clinical Analysis, Andrs Csillag, Humana Press (2005), pages 1-82, incorporated herein by reference). In brief, the middle ear consists of the eardrum and a small air-filled chamber containing three tiny bones known as the ossicles, which link the eardrum to the inner ear.
The inner ear (labyrinth) is a complex structure consisting of the cochlea, which is the organ of hearing, and the vestibular system, the organ of balance. The vestibular system consists of the saccule and the utricle, which determine position sense, and the semicircular canals, which help maintain balance.
The cochlea houses the organ of Corti, which consists, in part, of about 20,000 specialized sensory cells, called “inner ear hair cells” or “hair cells”. These cells have small hairline projections (cilia) that extend into the cochlear fluid. Sound vibrations transmitted from the ossicles in the middle ear to the oval window in the inner ear cause the fluid and cilia to vibrate. Hair cells in different parts of the cochlea vibrate in response to different sound frequencies and convert the vibrations into nerve impulses which are sent to the brain for processing and interpretation. The inner ear hair cells are surrounded by inner ear support cells. Supporting cells underlie, at least partially surround, and physically support sensory hair cells within the inner ear. Representative examples of support cells include inner rod (pillar cells), outer rod (pillar cells), inner phalangeal cells, outer phalangeal cells (of Deiters), cells of Held, cells of Hensen, cells of Claudius, cells of Boettcher, interdental cells and auditory teeth (of Huschke).
The spiral ganglion is the group of nerve cells that send a representation of sound from the cochlea to the brain. The cell bodies of the spiral ganglion neurons are found in the spiral structure of the cochlea and are part of the central nervous system. Their dendrites make synaptic contact with the base of hair cells, and their axons are bundled together to form the auditory portion of the eighth cranial nerve (vestibulocochlear nerve). The vestibular ganglion (also known as Scarpa's ganglion) is the ganglion of the vestibular nerve that contains the cell bodies of the bipolar primary afferent neurons whose peripheral processes form synaptic contact with hair cells of the vestibular sensory end organs.
US Patent Application Publication Nos. 20090162365 and 20110112168 are directed to siRNA compounds, compositions comprising same and to methods of use thereof for treating diseases and disorders related to expression of proapoptotic genes.
U.S. Pat. No. 7,825,099 relates to methods of treating hearing impairment by inhibiting a pro-apoptotic gene.
U.S. Pat. No. 8,088,359 and US Patent Application Publication No. 20120252868 relate to methods of treating hearing loss and phantom hearing.
US Patent Application Publication No. 20110142917 discloses non-invasive methods of delivering dsRNA molecules to the ear.
US Patent Application Publication No. 20110034534 relates to, inter alia, dsRNA molecules to target CAPNS1.
US Patent Application Publication No. 20110229557 relates to dsRNA molecules to various gene targets, including CASP2, useful in treating eye diseases.
PCT Patent Publication No. WO2011/163436 discloses dsRNA to target RHOA.
Tinnitus and Ménière's disease affects many individuals worldwide and current therapies have not been successful at preventing progression of neuronal degeneration and the attendant hearing loss. A therapeutic treatment, which would protect the inner ear neurons, including hair cells and spiral and vestibular ganglion cells, from damage and cell death (e.g. apoptosis), and thereby attenuate or prevent hearing loss in, for example, Ménière's patients would be highly desirable. It is, accordingly, an aspect to provide methods for neuroprotection of neurons in a subject's ear, including human subjects suffering from tinnitus or Ménière's disease or having similar symtoms, using dsRNA compounds not previously known to have such activity.